Aclaris Therapeutics : ITK Portfolio

EMPOWERING PATIENTS THROUGH

KINOME INNOVATION

Overview of ITK Portfolio

May 7, 2024

© Copyright 2024 Aclaris Therapeutics, Inc. All rights reserved

Cautionary Note Regarding Forward-Looking Statements

Any statements contained in this presentation that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements may be

identified by words such as "anticipate," "believe," "expect," "intend," "may," "plan," "potential," "will," and similar

expressions, and are based on Aclaris' current beliefs and expectations. These forward-looking statements include expectations regarding the development of ATI-2138, including the commencement of a Phase 2a clinical trial, and the development of a next-generation ITK selective inhibitor. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Risks and uncertainties that may cause actual results to differ materially include uncertainties inherent in the conduct of clinical trials, Aclaris' reliance on third parties over which it may not always have full control, Aclaris' ability to enter into strategic partnerships on commercially reasonable terms, the uncertainty regarding the macroeconomic environment and other risks and uncertainties that are described in the Risk Factors section of Aclaris' Annual Report on Form 10-K for the year ended December 31, 2023, and other filings Aclaris makes with the U.S. Securities and Exchange Commission from time to time. These documents are available under the "SEC Filings" page of the "Investors" section of Aclaris' website at www.aclaristx.com. Any forward- looking statements speak only as of the date of this presentation and are based on information available to Aclaris as of the date of this presentation, and Aclaris assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise.

This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and other data about our industry. These data involve a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.

ATI-2138: A First Generation Novel ITK/JAK3 Inhibitor for T Cell-Mediated Diseases

(Investigational Drug Candidate)

ATI-2138 Covalently Inhibits ITK and JAK3

ATI-2138 was designed to interact with the ATP site and covalently modifies CYS442 in ITK and CYS909 in JAK3

ATI-2138

CYS442

ATI-2138: Potential for Meaningful Differentiation

ATI-2138, by modulating both TCR signaling (via ITK blockade) and cytokine signaling (via JAK3 blockade), is a T cell focused modulator and potentially ideal for treating autoimmune diseases with high unmet medical need

ATI-2138 differs from both JAK inhibitors and ritlecitinib in important ways:

• Unlike approved JAK inhibitors, ATI-2138 is specific for JAK3 - does not inhibit other JAKs, including JAK2 which can lead to anemia
• Although both ATI-2138 and ritlecitinib are selective for JAK3, ATI-2138's potency on ITK is 20-80X greater than ritlecitinib

ATI-2138 Differentiation from Ritlecitinib

Dual ITK and JAK3 Inhibitors

ITK: HWB αCD3 Stimulated IFNγ ReleaseJAK3: HWB IL2 Stimulated IFNγ Release

• ATI-2138is 44.4x more potent than ritlecitinib for inhibiting αCD3 induced IFNγ production (ITK) and 5.4x more potent for inhibiting JAK3 dependent IL-2 induced IFNγ production in human whole blood
• At the FDA recommended 50 mg QD dose for alopecia areata, ritlecitinib plasma levels may not impact the anti-CD3 /IFNγ IC50 for any appreciable time
• In the ATI-2138 MAD study, the 5-40 mg BID doses inhibited up to 50%-90% of both ITK and JAK3 PD markers

ITK Modulates T Cell Differentiation and Activation

Skews T Helper Cell Differentiation Towards Th2 and Th17 Phenotypes

1. Sig Trans 2011:DOI:10.1155/2011/297868

ATI-2138Dose-Dependently Inhibited Adjuvant Induced Arthritis (AIA) in Rats

Ankle Diameter Swelling and Histology

ATI-2138Dose-Dependently Inhibited Inflammation in the Mouse T Cell Transfer Model of Inflammatory Bowel Disease

1. Study report SR03048; 2. CD4+CD45RB high naïve T cells injected to SCID mice; 3. *p<0.05, **p<0.01, ***p<0.001, vs Control group